DESCRIPTION: (from investigator's abstract) Glutamatergic synapses are responsible for an estimated 70% of synaptic transmission in the CNS, and the regulation of these synapses likely contributes to some forms of developmental plasticity and memory, as well as pathological processes such as excitoxicity. We will study mechanisms that regulate the strength of glutamatergic synapses in hippocampal neurons, focusing particularly on postsynaptic mechanisms. This studying will complement studies examining function of glutamate receptors in non-synaptic patches and in heterologous expression systems. The properties of single visualized glutamatergic synapses in cultured hippocampal neurons will be characterized under a variety of conditions producing changes in number or strength of synapses. Following up preliminary data showing that the properties of AMPA receptors change according to the total level of innervation of the neuron, we will characterize changes in number of receptors per postsynaptic site, time course of miniature excitatory post-synaptic currents, and kinetics of desensitization. Total synaptic innervation will be altered as a consequence of normal synaptogenesis and also with delayed synaptogenesis in synapsin-I knockout mice. Following up evidence that properties of synaptic AMPA receptors are regulated by neural activity, we will examine how crucial properties such affinity for glutamate, desensitization, and calcium permeability are altered when network activity is changed by exposure to tetrodotoxin and NMDA-receptor blockers. With knowledge of the elementary properties of glutamate receptor regulation, we will examine the molecular mechanisms of regulation by examining how the subunit composition of AMP receptors is altered during such regulation. A specific hypothesis to be tested is that there is differential expression and assembly of "flip" and "flop" versions of particular AMPA receptor subunits.